No-rinse chemical foam containing trifarotene, and use thereof in the treatment of acne

ABSTRACT

A self-foaming composition is described that includes trifarotene, for a no-rinse topical application and for application to the skin. The composition can include: at least one intermediate composition B including a gas-generating agent; at least one intermediate composition A including an agent for activating the gas-generating agent; and trifarotene or one of the pharmaceutically acceptable salts thereof being present in at least one of the intermediate compositions A and B. The composition is particularly intended for the treatment of acne. Also described is a kit or a single container including a plurality of compartments including such a composition.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application is a National Stage of PCT/EP2016/073009, filed Sep.27, 2016, and designating the United States (published on Apr. 6, 2017,as WO 2017/055292 A1), which claims priority under 35 U.S.C. § 119 toFrench Application No. 1559202, filed Sep. 29, 2015, each herebyexpressly incorporated by reference in its entirety and each assigned tothe assignee hereof.

The present invention relates to a leave-on topical product in the formof a foam for the pharmaceutical or cosmetic treatment of the skin,comprising trifarotene. Trifarotene is a novel retinoid and correspondsto3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′:3′,1″]terphenyl-4-carboxylicacid, of the same pharmacological class as tazarotene (arotenoids).

The present invention also relates to the use of the product accordingto the invention for treating acne.

Despite all the progress made, consumers are still in search ofcompositions intended for topical application that are more practicaland rapid. Foams make it possible to overcome the problems of toleranceby better control of the dose, by virtue of their spreading propertiesand their low density.

In addition, some compounds used in compositions intended for a knowntopical application may result in side-effects that may limit the useand thus the effectiveness thereof. For example, some active principleshave the major drawback of inducing irritation which may result inmediocre tolerance of the product. This may thus create, on the part ofthe patient, behavior of non-compliance with the treatment and ofdissatisfaction regarding said treatment.

There is thus a need to develop novel galenical forms that overcome thedrawbacks mentioned previously in terms of tolerance, efficacy andcompliance.

Furthermore, trifarotene, like many retinoids, is known to be poorlytolerated by consumers who are following a treatment for acne. Thistolerance is very variable as a function of the formulation serving asvehicle therefor. The patient also often has the impression that byapplying larger amounts of product, he will be cured faster. Thisbehavior leads to excessive irritation, non-compliance with the dosageand stoppage of the treatment.

There is also a need for novel galenical forms and in particular of foamor foaming composition type which allow better control of the dose andin which trifarotene is stable, well-tolerated, effective and pleasantto apply.

The composition according to the invention has the advantage of being inthe form of a foam which is generated at the time of use, and which isvery well tolerated.

After its application, the composition according to the invention is notremoved by rinsing.

One of the advantages of the composition of the invention is that it isparticularly well tolerated, despite the fact that it is not removed byrinsing, as is shown by the examples illustrating one of the methods ofevaluating the tolerance which are presented below.

Various methods exist for evaluating the tolerance of a pharmaceuticalor cosmetic product for cutaneous use, among which may be mentioned thein vivo “in used” or “human patch test” test but also the in vitro test,such as the test for measurement of the irritation on ReconstructedHuman Epidermis (RHE) described in the OECD TG 439 protocol. The lattermethod is described in detail in example 3.

Furthermore, the present invention also has the advantage of remainingon the surface of the skin (essentially stratum corneum and epidermis)so as to avoid adverse effects such as irritation and to obtain a foamthat is suitable for treating acne.

The efficacy of an active principle is associated with the release andthe penetration kinetics of the active agent through the skin. Theformulary composition plays its fundamental role as a vehicle for theactive principle so that said active principle can reach its therapeutictarget. The release-permeation test described in example 5 on ex-vivohuman skin highlights the advantage of applying a chemical foamcontaining trifarotene.

Thus, the formulations of the invention make it possible to obtain afoam composition which can reduce the adverse effects and especiallyirritation.

Foams or foaming compositions currently exist on the market. However,they all have a certain number of drawbacks:

This is because three types of foams or foaming compositions exist:

-   -   Aerosols, in which the foam is generated by a propellant gas but        with the drawback of being aerosols having the well-known risks        of the latter (contamination and breathing risks in particular).    -   Expanded creams, in which air bubbles are introduced into the        product via a particular manufacturing process. This process has        the drawback of being restricting at the industrial level and        requires major capital expenditure with regard to the packaging        equipment.    -   Foaming formulations which are low in foaming surfactants but        packaged a packaging equipped with a mechanical foam-generating        system (pump with grille of Pulvorex type). This type of        formulation requires the use of foaming surfactants, which may        lead to irritation in the case of leave-on products.

Thus, the need therefore remains to develop a pharmaceuticalcomposition, the galenical form of which is different from the knowngalenical forms, in order, inter alia, to provide compositions intendedfor topical application containing trifarotene in well-toleratedcompositions intended for topical application to human beings, inparticular leave-on compositions (i.e. the composition is not removed byrinsing after it has been applied).

The aim of the present invention is thus to provide a composition whichmeets these needs.

The Applicant has thus developed a novel pharmaceutical compositionintended for a leave-on topical application, which is in the form of afoam which advantageously does not contain any foaming surfactant. Theterm “foaming surfactant” defines surfactants which produce avoluminous, stable and creamy foam when they are mixed with wateraccording to tests that are well known to those skilled in the art.

The following constitute foaming surfactants: anionic surfactants,cationic surfactants, amphoteric surfactants and nonionic surfactants ofthe family of alkylpolyglucosides and glucamides.

The galenical form according to the invention has the advantage ofensuring good stability of trifarotene. Furthermore, this formulationadvantageously results in the production of a mild foam which is fullytolerated and non-irritant, which allows better coverage of the area tobe treated and which makes it possible to overcome the problems oftolerance by better control of the dose, by virtue of the spreadingproperties and the low density of the foam.

Finally, advantageously, this galenical form does not require, for theimplementation thereof, the use of propellant gases or aerosols. Thus,“aerosol” or “spray” foams are excluded from the scope of the invention.Likewise, the foams of the prior art of expanded cream and/or foamingformulation type requiring a mechanical foam-generating system (Pulvorextype) are also excluded from the invention.

Finally, a subject of the present invention is the cosmetic use of thecomposition according to the invention, by topical application of thiscomposition to the skin, and also a medicament intended for topicalapplication to the skin, comprising such a composition.

A subject of the present invention is also the composition according tothe invention, for its use in the treatment of acne.

The present invention will be described in greater detail in thedescription and the examples hereinbelow and in the light of the figuresappended to the present application.

FIG. 1 illustrates the production of a composition in foam form inaccordance with the invention. The left-hand photograph represents themoment of mixing (TO) and the right-hand photograph represents the foamobtained when the acid/base chemical reaction is complete.

FIG. 2 illustrates example 5 and represents the comparative results ofpenetration-permeation into the stratum corneum, the epidermis and thedermis of a foam composition according to the invention containing 0.01%by weight of trifarotene composed of the mixture of intermediatecompositions A2 and B3 described in example 1 (in a 50/50 weight ratio)and of a Reference in cream form containing 0.01% by weight oftrifarotene.

FIG. 3 also illustrates example 5 and represents the comparative resultsof penetration-permeation into the dermis of FIG. 1 on an enlargedscale.

The composition according to the invention is capable of taking the formof a foam solely by virtue of its composition, and may also be definedas a self-foaming composition for topical application.

A first subject of the present invention is consequently a compositioncontaining trifarotene, intended for leave-on topical application, whichis provided in the form of a foam, advantageously of semisolidconsistency, which advantageously does not contain any foamingsurfactant and which comprises a medium that is pharmaceuticallycompatible with leave-on topical application, in particular to the skinand integuments.

The term “composition in the form of a foam” (also referred tohereinbelow as a self-foaming composition) means a composition ofsemisolid consistency having an aerated form comparable to a foam.

The self-foaming composition according to the present inventioncomprises two intermediate compositions or formulations in variableproportions and in particular the ingredients below:

-   -   at least one intermediate composition or formulation A        comprising an agent for activating the gas-generating agent        defined below;    -   at least one intermediate composition or formulation B        comprising a gas-generating agent; and    -   trifarotene or one of the pharmaceutically acceptable salts        thereof contained in at least one of said intermediate        formulations A and B.

According to the invention, the composition is self-foaming, i.e. itfoams by simple mixing of the intermediate compositions A and B. Asubject of the invention is also the composition in foam form resultingfrom the mixing of said intermediate compositions A and B.

According to the invention, each intermediate composition (orformulation) may have a viscosity (measured at 25° C. and at atmosphericpressure) of between 1 cP and 500 000 cP, advantageously between 500 cPand 350 000 cP, measured with a conventional method of Brookfield RVDV-II type: spindle 6, speed 2.

According to the invention, the gas generated by the gas-generatingagent may be any physiologically compatible gas which allows theproduction of a foam, for instance carbon dioxide (CO₂) or oxygen (O₂).Preferably, the gas generated from the gas-generating agent is carbondioxide (CO₂).

According to the invention, since the gas concentration may vary, theamount of bubbles in the composition may vary and may thus give acomposition which may range from not very aerated to very stronglyaerated.

According to the invention, the term “agent for activating thegas-generating agent” means an ingredient which, by chemical reactionwith the gas-generating agent, releases a gas. Preferentially, anacid/base reaction is involved.

Thus, according to the invention, the self-foaming composition maypreferentially be in any form ranging from aerated to a highly expandedfoam.

The composition according to the invention is suitable for topicalapplication and may also comprise a physiologically acceptable medium,i.e. a medium that is compatible with the skin and integuments. It ispreferably a pharmaceutically acceptable medium.

In addition, the composition may comprise any active agent that may haveactivity, optionally therapeutic activity. These active agents may bechosen, inter alia, from emollients, humectants, free-radicalscavengers, anti-inflammatory agents, vitamins, depigmenting agents,antiacne agents, antiseborrheic agents, antifungal agents, keratolyticagents, sunscreens, slimming agents and skin-coloring agents.

According to the invention, the composition in foam form (i.e. ready tobe applied) may have a pH of between 2 and 8, preferentially between 4and 8.

Insofar as the intermediate composition(s) (or formulation(s)) requirestorage in at least two compartments for reasons of stability of theingredients, the present invention relates either to a singlecompartmentalized container (each compartment receiving one intermediateformulation) and preferably comprising two or three compartments, or toa kit comprising each intermediate formulation stored independently fromeach other and physically separated.

Intimate extemporaneous mixing (directly on the skin or on any othersupport) of the intermediate formulations makes it possible to obtainthe composition in foam form according to the invention.

More specifically, the intermediate composition (or formulation) A maybe in the form of a solution, an emulsion (lotion, cream,emulsifier-free cream, milk or fluid cream) or a gel. This compositionadvantageously contains the agent for activating the gas-generatingagent, preferentially an acid, in a sufficient amount (which may be inthe form of an acid/base buffer at acidic pH), which may be, as anonlimiting example, the citric acid/sodium citrate pair. Formulation Bmay be in the form of a solution, a gel or an emulsion (lotion, cream,emulsifier-free cream, milk or fluid cream). This compositionadvantageously contains, in a sufficient amount, a gas-generating agentwhich may in particular be sodium bicarbonate.

Thus, a subject of the invention is also a kit or a singlemulti-compartment container as defined previously, for theextemporaneous preparation of a composition in foam form according tothe invention, separately comprising at least two intermediateformulations (or intermediate compositions):

-   -   an intermediate formulation A comprising at least one agent for        activating the gas-generating agent; and    -   an intermediate formulation B comprising at least one        gas-generating agent;    -   trifarotene or one of the pharmaceutically acceptable salts        thereof being contained in at least one of said intermediate        formulations A and B.

Preferably, trifarotene is contained in the intermediate composition A.

Gas-Activating Agent:

The agent for activating the gas-generating agent (also referred to asthe “gas-activating agent”) is a compound which reacts with thegas-generating agent via a chemical reaction (preferably an acid/basereaction) which releases a gas.

It is advantageously an acid, a partially salified polyacid salt or abuffer solution of a weak acid and of its conjugate base, or a mixtureof such compounds.

According to the invention, the acid/base buffer of said acid may be anyacid/base buffer of the weak acid, for instance a citric acid/sodiumcitrate buffer or a tartaric acid/sodium tartrate buffer. Mention willpreferably be made of α-hydroxy acids, which are weak acidspreferentially with a pKa of between 2 and 6, such as citric acid,tartaric acid, malic acid or lactic acid, but also phosphoric acid andpyrophosphoric acid and optionally the partially salified salts thereof,such as disodium pyrophosphate or sodium dihydrogen phosphate, alsoknown as monosodium phosphate.

Preferentially, according to the invention, the gas-activating agent ischosen from a tartaric acid/tartrate salt (for example sodium tartrate)buffer; a citric acid/sodium citrate buffer alone; phosphoric acid,monosodium phosphate, disodium pyrophosphate, which are alone or as amixture with a citric acid/sodium citrate buffer.

According to a very preferred embodiment, the gas-activating agent is acitric acid/sodium citrate buffer, alone or as a mixture with monosodiumphosphate and/or disodium pyrophosphate.

In compositions for sensitive skin or for damaged skin, such as acneicskin, the content of citric acid/sodium citrate is preferably less thanor equal to 2.4%, relative to the total weight of the intermediatecomposition A, so as to limit any risk of stinging. In order to improvethe tolerance and to avoid the sensation of stinging, preferably, thecitric acid/sodium citrate buffer is used as a mixture with disodiumpyrophosphate or sodium dihydrogen phosphate.

According to the invention, said gas-activating agent may be present inthe intermediate formulation A in an amount that may range from 0.001%to 95% by weight relative to the total weight of the intermediatecomposition A.

Gas-Generating Agent:

The term “gas-generating agent” means any agent which has the propertyof generating a gas via a chemical reaction. Mention will be made inthis regard of any compound which, when it is mixed with a weak acid,can form a gas via a chemical reaction equivalent to the following:NaHCO₃+RCOOH→RCOONa+H₂O+CO₂

According to the invention, the gas generated from the gas-generatingagent present in the intermediate composition B is preferably carbondioxide (CO₂).

According to the invention, the gas-generating agent is preferablychosen from sodium bicarbonate, potassium bicarbonate, sodium carbonateand potassium carbonate, and mixtures thereof.

Preferentially, according to the invention, the intermediate formulationB comprises an agent which generates carbon dioxide, this agentparticularly preferably being sodium bicarbonate.

Said gas-generating agent may be present in the intermediate formulationB in an amount ranging from 1% to 10% by weight and preferentially from2% to 8% by weight, relative to the weight of the intermediatecomposition B.

According to the invention, the intermediate formulation A may have anacidic pH, advantageously of between 1.0 and 6.0, and the intermediateformulation B may have a basic pH, advantageously of between 7 and 12.

According to the invention, one (or more) intermediate formulation(s)comprise trifarotene, in unmodified form or in salt form, in an amountcorresponding to 0.00001% to 20% by weight of trifarotene in acid form(i.e.3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′:3′,1″]terphenyl-4-carboxylicacid) relative to the total weight of the total composition.

Preferably, the total composition (mixture of the intermediate offormulation A with the intermediate of formulation B) containstrifarotene, in unmodified form or in salt form, in an amountcorresponding to 0.00001% to 1% by weight, preferentially from 0.0001%to 0.1% by weight and more preferentially from 0.001% to 0.1% by weightof trifarotene in acid form relative to the weight of the totalcomposition.

In the present description, the term “total composition” or “totalformulation” means the composition of the product in foam form aftersaid intermediate compositions have been mixed. Preferably, trifaroteneis contained in intermediate composition A which has bettercompatibility with the active agent.

In fact, the Applicant has discovered that trifarotene could in certaincases have a lesser compatibility with the ingredients constituting theformulation B, and most particularly with sodium bicarbonate.

The intermediate formulation A may be in any galenical form that iscompatible with the galenical form desired for the final compositionobtained by mixing formulation A with formulation B.

The intermediate formulation B may be in any galenical form that iscompatible with the galenical form desired for the final compositionobtained by mixing formulation B with formulation A. Advantageously,formulation B may be a gel, a solution, a suspension or an emulsion(cream, surfactant-free cream, lotion, milk or fluid cream), preferablyan emulsion.

According to one embodiment of the invention, one of the twointermediate formulations (i.e. intermediate formulation A orintermediate formulation B) is in the form of a gel. In this embodiment,the other intermediate formulation is preferably not in gel form.

Each intermediate formulation of the kit or of the multi-compartmentcontainer as defined previously in accordance with the inventioncomprises a physiologically acceptable medium which conveys thecompound(s) and which is chosen such that the compounds are capable ofreacting with each other to form a self-foaming composition during themixing of at least the intermediate formulations A and B.

Thus, the extemporaneous mixing of at least two formulations, forexample formulation A and formulation B, creates the composition in foamform according to the invention.

During the mixing of the two formulations A and B, the gas-generatingagent, such as sodium bicarbonate, reacts with the gas-activating agent,such as the acid, and thus gives in particular the salt corresponding tothe acid, water and CO₂ gas. It is this gas, trapped in the bubbles ofthe composition, which creates the foam which characterizes theself-foaming composition of the invention.

Thus, by mixing at least intermediate formulation A and intermediateformulation B, the foam composition, referred to as the totalcomposition, according to the invention is obtained. Unreactedgas-activating agent and/or gas-generating agent may, of course, remainin the composition obtained after mixing at least formulations A and B.

Advantageously, the kit or the single multi-compartment containeraccording to the invention may be designed so that, during thepreparation of the composition according to the invention, theintermediate formulations A and B can be mixed in an A/B weight ratioranging from 0.5 to 2, preferentially from 0.5 to 1.5, morepreferentially close to 1 (i.e. from 0.9 to 1.1) and even morepreferentially 1. This means that the kit can be designed tosimultaneously release doses (by weight) of the intermediatecompositions A and B that may be in a weight ratio ranging from 2 dosesof B per 1 dose of A to 2 doses of A per 1 dose of B, preferably from 2doses of B per 1 dose of A to 3 doses of A per 2 doses of B. Accordingto a preferred embodiment of the invention, the kit is designed tosimultaneously release 1 dose by weight of A and 1 dose by weight of B.

According to the invention, the kit may be in any form that iscompatible with, on the one hand, separate storage of the intermediateformulations A and B and, on the other hand, the ability to performextemporaneous mixing of A and B.

For example, the intermediate formulations A and B may be packaged in acase with at least two separate compartments, each containing A or B.

According to another aspect, the kit may be in the form of a syringehaving at least two separate bodies, each equipped with a piston, saidtwo bodies containing the respective formulations A and B and beingdesigned to simultaneously release, by exerting a force on the piston,the desired doses of formulations A and B.

The invention also relates to a process for preparing a compositionaccording to the invention, characterized in that, in order to obtainthe composition in foam form, an intermediate formulation A and anintermediate formulation B of the kit as are defined above are mixedextemporaneously in relative weight proportions A/B that may range from0.5 to 2, preferentially from 0.5 to 1.5 and more preferentially 1.

In order to obtain an optimum foam (final composition), the inventorsexperimentally sought the optimum contents of gas-generating agent(preferably sodium bicarbonate) and of gas-activating agent (preferablycitric acid and/or disodium pyrophosphate and/or sodium dihydrogenphosphate or monosodium phosphate).

Thus, it was determined experimentally that when the gas-activatingagent is citric acid, the citric acid/sodium bicarbonate weight ratio isadvantageously between 0.1 and 2, preferentially between 0.5 and 1 andvery preferably equal to 0.7.

Similarly, it was determined experimentally that when the gas-activatingagent is disodium pyrophosphate, the disodium pyrophosphate/sodiumbicarbonate weight ratio is between 0.5 and 5, preferentially between 1and 3 and very preferably equal to 2.4.

Similarly, it was determined experimentally that when the gas-activatingagent is sodium dihydrogen phosphate, the sodium dihydrogen phosphatemonohydrate/sodium bicarbonate weight ratio is between 0.5 and 5,preferentially between 1 and 3 and very preferably equal to 2.

The sodium bicarbonate/citric acid, sodium bicarbonate/sodiumpyrophosphate and sodium bicarbonate/sodium hydrogen phosphate ratiosare illustrated in example 4.

Surprisingly, the citric acid/sodium citrate, disodium pyrophosphate orsodium dihydrogen phosphate combination and a gelling system that iscompatible with the galenical form made it possible to obtain aformulation with very stable physicochemical properties and in whichtrifarotene is particularly stable, does not generate any unpleasantsensation on the skin and allows the liberation of gas and thus thecreation of foam.

Example 2B below shows that the compositions according to the presentinvention have both excellent physical and chemical stability.

A composition is regarded as being physically stable when itsorganoleptic characteristics, its pH, its viscosity and the homogeneityof trifarotene do not change over time under various temperatureconditions: room temperature (RT) and 40° C.

According to the invention, room temperature corresponds to atemperature ranging from 15° C. to 25° C.

A composition is regarded as being chemically stable when the content ofactive principle it contains does not change over time under varioustemperature conditions (RT and 40° C.). According to the invention, thecomposition is regarded as being stable when the content of trifarotene(expressed by weight relative to the weight of the intermediateformulation) is included in the specifications ranging from 90% to 110%.

The composition according to the invention may also comprise one or moreagents chosen from dispersants, stabilizers, preserving agents, fattysubstances, thickeners, dyes, fragrances, surfactants, gelling agents,complexing agents, neutralizers, non-foaming emulsifying agents,fillers, sequestrants, reducing agents, odor maskers, plasticizers,softeners, moisturizers, pigments, clays, mineral fillers, mineralcolloids, polymers, proteins, nacreous agents, waxes, oils, for instanceparaffins or silicones, fatty acids, solid esters of fatty alcohols orof fatty acids, gums and wetting agents.

Water-soluble dyes, such as FD&C Blue 1 (of empirical formulaC₃₇H₃₄N₂Na₂O₉S₃), and liposoluble dyes such as Sudan Red III or NileRed, have the advantage of coloring one of the formulationintermediates. This coloring makes it possible to monitor thesatisfactory mixing of the two formulation intermediates and tohighlight the formation of the foam. This coloring is especiallypresented in the examples and in FIG. 1.

Gelling Agents for the Intermediate Formulation Comprising the GasActivator

The intermediate composition A advantageously containing at least onegas-activating agent preferably contains at least one gelling agentand/or suspending agent.

Formulation A may contain large amounts of acid and of electrolytes. Theviscosity and the suspending power of these formulations are oftendifficult to ensure over time.

As nonlimiting examples of gelling agents and/or suspending agents whichare resistant simultaneously to electrolytes and to acidic pH values andwhich may be included in the compositions A according to the invention,mention may be made of ready-to-use mixtures, such as thepolyacrylate-13 & polyisobutene & polysorbate 20 mixture sold by SEPPICunder the name Sepiplus 400®, the acrylamide/sodium acryloyldimethyltaurate copolymer & isohexadecane & polysorbate 80 mixture sold bySEPPIC under the name Simulgel 600®, polysaccharides with, asnonlimiting examples, xanthan gum, such as Xantural 180® sold by thecompany Kelco, gellan gum sold under the name Kelcogel® by the companyKelco, sclerotium gum sold under the name Amigel® by Alban MullerIndustrie, guar gum and derivatives thereof, such as the hydroxypropylguar sold under the name Jaguar HP-105@ by Rhodia, cellulose andderivatives thereof, such as microcrystalline cellulose and sodiumcarboxymethyl cellulose sold under the name Blanose CMC 7H4XF® by thecompany Hercules, hydroxypropylmethylcellulose, in particular theproduct sold under the name Methocel E4M® Premium by the company DowChemical, or hydroxyethylcellulose, in particular the product sold underthe name Natrosol HHX 250® by the company Aqualon, the family of themagnesium aluminum silicates, such as Veegum K®, Veegum Plus® or VeegumUltra® sold by the company Vanderbilt, bentonite sold under the namePolargel® HV, the family of modified starches, such as the modifiedpotato starch sold under the name Structure Solanace®, the family ofcarrageenans, in particular divided into four main families: κ, λ, β andω, such as the Viscarin® and Gelcarin® products sold by the companyIMCD. Alternatively, polyvinyl alcohol, also known under theabbreviation PVA, sold by Merck under the name Polyvinyl Alcohol 40-88®.Preferably, Veegum K® and Xantural 180® will be used in combination.

The gelling agent as described above may be used at preferentialconcentrations ranging from 0.001% to 15% and more preferentiallyranging from 0.15% to 5% by weight relative to the weight of theintermediate formulation A.

Gelling Agents for the Intermediate Formulation Containing the GasGenerator

As nonlimiting examples of gelling agents and/or suspending agentsand/or gelling agents that are simultaneously resistant to electrolytesand two basic pH values and which may be included in the intermediatecompositions B according to the invention, mention may be made ofacrylic acid polymers such as the acrylates/C10-30 alkyl acrylatecrosspolymer such as the “electrolyte-insensitive” carbomers sold underthe name Ultrez 20®, Ultrez 10®, Carbopol 1382® or Carbopol ETD2020NF®,Aqua SF1® sold by the company Lubrizol, the ammonium acrylate/acrylamidecopolymer & polyisobutene & polysorbate 20 mixture sold by SEPPIC underthe name Sepiplus 265®, the acrylamide/sodium acryloyldimethyl tauratecopolymer & isohexadecane & polysorbate 80 mixture sold by SEPPIC underthe name Simulgel 600®, polysaccharides with, as nonlimiting examples,xanthan gum, such as Xantural 180® sold by the company Kelco, gellan gumsold under the name Kelcogel® by the company Kelco, sclerotium gum soldunder the name Amigel® by Alban Muller Industrie, guar gum andderivatives thereof, such as the hydroxypropyl guar sold under the nameJaguar HP-105® by Rhodia, cellulose and derivatives thereof, such asmicrocrystalline cellulose and sodium carboxymethyl cellulose sold underthe name Blanose CMC 7H4XF® by the company Hercules,hydroxypropylmethylcellulose, in particular the product sold under thename Methocel E4M® Premium by the company Dow Chemical, orhydroxyethylcellulose, in particular the product sold under the nameNatrosol HHX 250® by the company Aqualon, the family of the magnesiumaluminum silicates, such as Veegum K®, Veegum Plus® or Veegum Ultra®sold by the company Vanderbilt, bentonite sold under the name Polargel®HV, the family of modified starches, such as the modified potato starchsold under the name Structure Solanace® or the tapioca meal known underthe name Naviance Tapioca P® sold by AkzoNobel, or the family ofcarrageenans, in particular divided into four main families: κ, λ, β andω, such as the Viscarin® and Gelcarin® products sold by the companyIMCD. Preferably, Veegum K® and Xantural 180® will be used incombination.

The gelling agent as described above may be used at preferentialconcentrations ranging from 0.001% to 15% and more preferentiallyranging from 0.15% to 5% by weight relative to the weight of theintermediate formulation B.

Humectants

Among the humectants and/or emollients which may act as skin moisturizerand facilitate the application of the formulation, use is optionallymade, without this list being limiting, of compounds such as a polyolthat is water-miscible at room temperature (25° C.) chosen especiallyfrom polyols especially containing from 2 to 20 carbon atoms, preferablycontaining from 2 to 10 carbon atoms and preferentially containing from2 to 6 carbon atoms, such as glycerol, glycol derivatives such aspropylene glycol, butylene glycol, pentylene glycol, hexylene glycol,dipropylene glycol, diethylene glycol and mixtures thereof, but alsosugars (for example glucose or lactose), polyethylene glycols (PEG) (forexample Lutrol E400®), urea, and amino acids (for example serine,citrulline, arginine, asparagine or alanine).

As preferred humectant and/or emollient, mention may be made of glyceroland propylene glycol.

The humectants may be used, alone or in combination, at preferentialconcentrations ranging from 0.001% to 30% and more preferentiallyranging from 0.01% to 10% by weight relative to the weight of the totalformulation.

Chelating Agents

Among the chelating agents, mention may be made, as nonlimitingexamples, of ethylenediaminetetraacetic acid (EDTA),diethylenetriaminepentaacetic acid (DTPA),ethylenediaminebis(O-hydroxyphenylacetic acid) (EDDHA),hydroxy-2-ethylenediaminetriacetic acid (HEDTA),ethyldiaminebis(O-hydroxy-p-methylphenyl)acetic acid (EDDHMA) andethylenediaminebis(5-carboxy-2-hydroxyphenyl)acetic acid (EDDCHA).

As preferred chelating agent, mention may be made ofethylenediaminetetraacetic acid (EDTA) sold especially under the nameTitriplex III®; it may be used at preferential concentrations rangingfrom 0.001% to 1% and more preferentially from 0.05% to 0.1% by weightrelative to the weight of the total formulation.

Excipients with Complementary Properties

The composition according to the invention may contain one or morecosmetic active agents, for instance, as nonlimiting examples, allantoinwith anti-irritant properties, antiacne zinc gluconate, dipotassiumglycyrrhizate for its anti-inflammatory properties, or alternatively thecicatrizing agent α-bisabolol or dimethyl isosorbide for itspro-penetrating properties.

Fillers and Particles

Fillers and/or particles may be used to stabilize and boost the foam.Some of them have the specific property of being positioned at thewater/air interface and of thus stabilizing this interface. Fillers thatmay be mentioned include talc, metal oxides such as zinc oxide, titaniumdioxide TiO2 T2000 sold by the company Merck under the name Eusolex®T-2000, clays such as laponites, bentones or bentonites, but alsocellulose ethers such as Methocel® K100 LV sold by the company Dow,silicas such as Aerosil® R972 sold by the company Evonik or Silice HDK®H13L sold by Wacker; they may be used at concentrations ranging from0.01% to 10% by weight relative to the weight of the total formulation.

Oils of the Fatty Phase

The composition according to the invention may also comprise a fattyphase. This fatty phase may be present in one and/or the other of theintermediate compositions A and B. Depending on the galenical form ofthe intermediate formulations, the fatty phase may represent from 0% to95% by weight relative to the weight of each intermediate formulation.

The fatty phase of the composition according to the invention maycomprise, for example, plant, mineral, animal or synthetic oils,silicone oils, and mixtures thereof.

As examples of mineral oils, mention may, for example, be made of liquidparaffins of various viscosities, such as Primol 352®, Marcol 82® andMarcol 152® sold by the company Esso.

As plant oils or derivatives thereof, mention may be made of sweetalmond oil such as Prunus Amygdalus Dulcis (sweet almond) oil suppliedby SICTIA, palm oil, soybean oil, sesame oil, sunflower oil, olive oiland apricot kernel oil and esters thereof such as the product ApricotKernel Oil PEG-6 Ester (Labrafil M1944CS).

As animal oils or the substitute thereof of plant origin, mention may bemade of lanolin, squalene, fish oil with, as a derivative, theperhydrosqualene sold under the name Sophiderm® by the company Sophim.

As synthetic oils, mention may be made of an ester such as cetearylisononanoate, for instance the product sold under the name Cetiol SN PH®by the company Cognis France, isononyl isononanoate such as Dub ININ®sold by the company Stéarineries Dubois, diisopropyl adipate, forinstance the product sold under the name Crodamol DA® by the companyCroda, isopropyl palmitate, for instance the product sold under the nameCrodamol IPP® by the company Croda, and caprylic/capric triglyceride,such as Miglyol 812® sold by the company Univar. As hydrogenatedpolyisobutenes, mention may be made of the Parleam® products sold by thecompany Rossow, PPG-15 stearyl ether (Arlamol PS15 E) supplied by CRODAor PPG-11 stearyl ether (Arlamol PS11E-LQ) supplied by Gattefossé.

As silicone oils, mention may be made of a dimethicone, for instance theproduct sold under the name Q7-9120 Silicone Fluid® with a viscosityfrom 20 cSt to 12 500 cSt, by the company Dow Corning, or acyclomethicone, for instance the product sold under the nameST-Cyclomethicone 5NF®, also by the company Dow Corning.

These oils may be present, alone or in combination, in contents rangingfrom 0.5% to 50% by weight and preferentially from 2% to 30% by weightrelative to the weight of the total composition.

Nonliquid Fatty Substances

The composition according to the invention may also comprise solid fattysubstances such as natural or synthetic waxes, fatty acids such asstearic acid, fatty alcohols such as Speziol C18® Pharma or Speziol C16®sold by the company Cognis, and texturing agents of tribehenate type,such as Compritol 888® sold by the company Gattefossé or hydrogenatedcastor oils such as Cutina HR® sold by the company Cognis or glycerylstearate such as Geleol® sold by the company Gattefossé or DC 9045Elastomer Blend® sold by the company Dow Corning.

These nonliquid fatty substances may be used alone or as a mixture from0% to 30% by weight relative to the weight of the total formulation.However, exceptional foam quality has been observed when fatty alcoholsof formula CH3(CH2)nOH (n is between 11 and 23) are present in contentsof greater than 1% by weight relative to the weight of the totalformulation.

Nonionic Emulsifiers

The composition according to the invention may also comprise one or morenonionic emulsifiers.

Preferred emulsifiers that may be mentioned include hydrophilicemulsifiers such as glyceryl stearate (and) PEG-100 stearate sold underthe name Arlacel 165FL® by the company Uniqema, lipophilic emulsifierssuch as propylene glycol monocaprylate (Capryol 90) supplied byGattefossé, propylene glycol laurate (Lauroglycol FCC) supplied byGattefossé, sorbitan sesquioleate (Arlacel 83VPharma) supplied by Croda,Glucate SS® and Glucamate SSE®, polyoxyethylene (21) stearyl ether soldunder the name Brij 721® by the company Uniqema or also in the samefamily Brij S2® and Brij S20®. The self-emulsifying wax sold by Crodaunder the name of Polawax NF® or else laureth-4. Mention may also madeof nonionic non-foaming emulsifiers with a high HLB, sorbitan esterssuch as POE(20) sorbitan monooleate sold under the name Tween 80®(HLB=15), POE(20) sorbitan monostearate sold under the name Tween 60®(HLB=14.9), fatty alcohol ethers such as POE (21) stearyl ether(HLB=15.5), or ceteareth-20 sold under the name of Eumulgin B2 PH® byCognis (HLB of 15.5), or nonionic emulsifiers with a low HLB, sorbitanesters, such as sorbitan monostearate (sold under the name of Span 60®by Uniqema), glycerol esters such as glyceryl monostearate (Cutina GMS®from Cognis), sucrose esters with a low HLB, such as sucrose distearate.In another form according to the invention, the emulsifiers that may beused are polyglycerol esters. They are esters of polyglycerolated fattyacids obtained by condensation of glycerol. Glycolipid emulsifiers, suchas Montanov 202® sold by the company SEPPIC. Some emulsifiers may besold in the form of a mixture, such as Emulium Kappa® and Emulium Delta®sold by Gattefossé. These emulsifiers may be used, alone or as amixture, so that the HLB of the system is greater than 12 andpreferentially greater than 15.

Such emulsifiers may be used at between 0.01% and 30% by weight,relative to the weight of the total composition, preferentially between0.1% and 15% and more preferentially between 0.5% and 7%.

Preserving Agents:

Examples of preserving agents that may be mentioned include benzalkoniumchloride, bronopol, chlorhexidine, chlorocresol and derivatives thereof,ethyl alcohol, phenoxyethanol, potassium sorbate, diazolidinyl urea,benzyl alcohol, parabens and sodium benzoate, or mixtures thereof.

As preferred preserving system, mention may be made of the combinationphenoxyethanol and pentylene glycol or sodium benzoate.

The examples that follow illustrate the invention without limiting itsscope.

EXAMPLES Example 1: Formulation Examples Formulation Examples A:Intermediate Compositions a Containing the Gas-Activating Agent

Intermediate formulations A were prepared according to the followingprocess:

Step 1: At a temperature above 60° C., add the gelling agents withstirring to the main water phase.

Step 2: With stirring, introduce trifarotene into an additional phase.

Step 3 (optional): in parallel, melt the fatty phase at a temperatureabove 60° C. This fatty phase is composed of the emulsifiers, the waxesand the emollient oils.

Step 4 (optional): At a temperature above 60° C., prepare the emulsionby adding the fatty phase to the main phase.

Step 4: Add the additional phase containing trifarotene to the mainphase.

Step 5: Cool and add the additives such as the dye, the cosmetic activeagents and the humectants.

In the formulation examples below, the amounts are expressed relative tothe weight of the intermediate formulation rather than relative to theweight of the total formulation.

Example A1

% by INCI name weight WATER QS 100 XANTHAN GUM 0.5 ACRYLAMIDE, AMPS 1.5COPOLYMER DISPERSION 40%/ ISOHEXADECANE/ POLYSORBATE 80 CETOSTEARYL 3ALCOHOL CYCLOPENTASILOXANE 2 CETEARETH-20 3 GLYCERYL 3 DIBEHENATE PPG-11STEARYL 5 ETHER DISODIUM EDTA 0.1 CITRIC ACID 1.75 SODIUM CITRATE 1.3DISODIUM 6 PYROPHOSPHATE PHENOXYETHANOL 1 TRIFAROTENE 0.02

Example A2

% by INCI Name weight WATER QS 100 XANTHAN GUM 0.5 ACRYLAMIDE, AMPS 1.5COPOLYMER DISPERSION 40%/ ISOHEXADECANE/ POLYSORBATE 80 CETOSTEARYLALCOHOL 3 CYCLOPENTASILOXANE 2 CETEARETH-20 3 GLYCERYL DIBEHENATE 3PPG-11 STEARYL ETHER 5 DISODIUM EDTA 0.1 CITRIC ACID 1.5 SODIUM CITRATE0.5 SODIUM DIHYDROGEN 6.2 PHOSPHATE PHENOXYETHANOL 1 TRIFAROTENE 0.02

Example A5

% by INCI Name weight WATER QS 100 DISODIUM EDTA 0.1 XANTHAN GUM 0.7MAGNESIUM ALUMINUM 2.5 SILICATE DISODIUM 6 PYROPHOSPHATE CITRIC ACID 1.8SODIUM CITRATE 1.3 POLOXAMER 124 0.2 TRIFAROTENE 0.02 PROPYLENE GLYCOL4.0

Example A7

% by INCI Name weight WATER QS 100 DISODIUM EDTA 0.1 XANTHAN GUM 0.7MAGNESIUM 2.5 ALUMINUM SILICATE SODIUM BENZOATE 0.2 DISODIUM 7.2PYROPHOSPHATE CITRIC ACID 1.4 SODIUM CITRATE 1 POLOXAMER 124 0.2TRIFAROTENE 0.02 PROPYLENE GLYCOL 4.0

Formulation Examples B: Intermediate Compositions B Comprising theGas-Generating Agent

The intermediate formulations B were prepared according to the followingprocess:

Step 1′: At a temperature above 60° C., add the gelling agents withstirring to the main water phase.

Optional step 2′: In parallel, heat the fatty phase (containing theoils, the waxes and the surfactants) to a temperature above 60° C.

Optional step 3′: At a temperature above 60° C., prepare the emulsion byadding the fatty phase to the main phase.

Step 4′: Add the additives such as the preserving agents or ethanol at atemperature suitable for the additive.

Step 5′: Neutralize the mixture.

Step 6′: At a temperature below 40° C., add the sodium bicarbonate.

Example B1

% by INCI Name weight WATER QS 100 MAGNESIUM 2.5 ALUMINUM SILICATEXANTHAN GUM 0.6 TRIETHANOLAMINE 1.2 SODIUM 5 HYDROGEN CARBONATEPHENOXYETHANOL 0.8

Example B2

% by INCI Name weight WATER QS 100 MAGNESIUM ALUMINUM 2.5 SILICATEXANTHAN GUM 0.5 CETOSTEARYL ALCOHOL 3 CETEARETH-20 3 GLYCERYL DIBEHENATE3 PPG-11 STEARYL ETHER 5 CYCLOPENTASILOXANE 2 SODIUM HYDROXIDE 0.09SODIUM HYDROGEN 5 CARBONATE PHENOXYETHANOL 1

Example B3

% by INCI Name weight WATER QS 100 DISODIUM EDTA 0.1 MAGNESIUM 2.5ALUMINUM SILICATE XANTHAN GUM 0.7 SODIUM 0.09 HYDROXIDE SODIUM 5HYDROGEN CARBONATE PHENOXYETHANOL 0.8

Example B7

% by INCI Name weight WATER QS 100 MAGNESIUM ALUMINUM 2.5 SILICATEXANTHAN GUM 0.5 CETEARETH-20 3 CETOSTEARYL ALCOHOL 3 GLYCERYL DIBEHENATE3 CAPRYLIC/CAPRIC 6 TRIGLYCERIDE SODIUM HYDROXIDE 0.09 PHENOXYETHANOL0.8 SODIUM HYDROGEN 5 CARBONATE

The mixtures in a 1:1 weight ratio of the intermediate compositions Aand B described above are represented in the table below. A cross at theintersection of two formulation intermediates indicates that the mixturewas tested and generated a foam having the desired properties.

Formulation B Formulation A B1 B2 B3 B7 A1 X X X X A2 X X X X A5 X X A7X X

Example 2A: Foam Density Measurements

Starting with the formulation examples described in example 1, foamdensity measurements were taken at the time of placing in contact of thetwo intermediate formulations A and B (TO) and then when the chemicalreaction generated by the placing in contact of the two compositions iscomplete:

Density placebo formulation A5, i.e. without trifarotene (but with bluecolorant)=1.108

Density formulation B7=1.021

Placebo foam A5/B7 (50/50)=0.290

The foam density measurement shows that the volume increased by a factorof 4 and was confirmed by the photographs in FIG. 1. The left-hand photorepresents the moment of mixing (TO) and the right-hand photo representsthe foam obtained when the acid/base chemical reaction is complete.

Example 2B: Stability

Tables Ia and Ib below collate the physical stability data of theintermediate formulations A1 and A2 described in example 1, containingtrifarotene.

Formulation A1 T0 T1 Month T3 Months T6 Months Macroscopic Bright whiteRT Complies Complies Complies appearance homogeneous 40° C. CompliesComplies Complies cream Microscopic Emulsion oil RT Complies CompliesComplies observations droplets less 40° C. Complies Complies CompliesX400 than 2.5 μm Brookfield RV 27360 RT — — 23000 DVII 40° C. — — 24800Spindle 5, speed 5 Viscosity cP pH 3.85 RT 4.01 3.75 3.76 40° C. 3.89 —3.76 Formulation A2 T0 T1 Month T2 Months T6 Months Macroscopic Brightwhite RT Complies Complies Complies appearance homogeneous 40° C.Complies Complies Complies cream Microscopic Emulsion oil RT CompliesComplies Complies observations droplets less 40° C. Complies CompliesComplies X400 than 5 μm Viscosity cP — RT 5902 6119 6119 Brookfield LV 5° C. 5375 6287 — DVII 40° C. 7414 6071 4900 Spindle 66, speed 50 pH3.45 RT 3.45 3.44 3.42  5° C. 3.47 3.56 — 40° C. 3.46 3.45 3.48

Table II below details the chemical stability data for trifarotene inintermediate formulation A1.

T2 T3 Formulation A1 T0 T1 Month Months Months % w/trifarotene 104.9 RT— 104 (HPLC) 40° C. 106.3 105.7 106

Example 3: Comparative Study of Measurement of Irritation

Study Protocol.

The study is performed according to the OECD TG 439 protocol in forcefor the short application time (RHE/product contact time 15 min). Thisprotocol is appropriate for a long application time (RHE/product contacttime 18 h).

The objective of this study is to evaluate the tolerance of the supportsof the complete and intermediate formulations on reconstructed humanepidermides (RHE, Episkin model) through:

-   -   evaluation of the reduction of MTT (cell viability)    -   measurement of the release of IL-1alpha (irritation marker)

The formulations tested are:

-   -   An intermediate a composition of acidic formulation: placebo        example A7 (i.e. not containing trifarotene),    -   An intermediate composition of basic formulation: example B7,    -   The complete formulation composed of the mixture: A7 placebo+B7        (in a 50/50 weight ratio),    -   A commercial reference in cream form.

Study Results:

Conclusion Short exposure Long exposure Irritant Mixture testedViability (%) Viability (%) potential B7 89.8 93.3 Non-irritant A7placebo 86.0 84.5 Non-irritant Complete formulation 95.8 83.4Non-irritant Commercial ref. 99.8 91.1 Non-irritant Short exposure Longexposure Mixture tested IL-1a vs control IL-1a vs control B7 1.5 2.0 A7placebo 2.2 2.3 Complete formulation 1.9 3.1 Commercial ref. 2.4 3.6

The MTT measurements according to the OECD protocol in force indicatethat all the formulations tested are non-irritant.

The assay of IL-1a of the complete formulation according to theinvention after a short exposure time and a long exposure time shows alower content of irritation markers than after application of thecommercial reference.

Example 4

The ideal content of citric acid, sodium pyrophosphate and sodiumdihydrogen phosphate monohydrate to react with 5% of sodium bicarbonatewas established empirically. The values are expressed as weight/weightpercentages relative to the weight of each of the two intermediateformulations.

Ratio 1 Ratio 2 Ratio 3 Sodium bicarbonate   5%  5%   5% Citric acid3.5% — — Disodium pyrophosphate — 12 — Sodium dihydrogen — 7.2%phosphate monohydrate

In order for the pH of the formulation containing the gas activator tohave optimum compatibility with the skin, sodium citrate was added so asto create a citric acid/sodium citrate buffer.

Part of the citric acid/sodium citrate buffer may advantageously bereplaced with disodium pyrophosphate and vice versa like the contentscited by way of example in the table below:

Table III: the values are expressed as weight/weight percentagesrelative to the weight of each of the two intermediate formulations.

E 1 E2 E 3 E 4 E 5 E 6 E 7 Sodium  5% 5%  5%  5%  3%   3%  3%bicarbonate Citric acid 3.5% 1.75%   1.4% 0 2.1% 1.05% 0 Sodium citrate2.7% 1.3%   1% 0 1.6% 1.15% 0 Disodium 0 6% 7.2% 12% 0  3.6% 7.2%pyrophosphate

Part of the citric acid/sodium citrate buffer may advantageously bereplaced with sodium dihydrogen phosphate monohydrate and vice versa,like the contents cited by way of example in table IV below:

Table IV: the values are expressed as weight/weight percentages relativeto the weight of each of the two intermediate formulations.

E1 E8 E9 Sodium bicarbonate   5%   5%  5% Citric acid 3.5% 1.5% 0 Sodiumcitrate 2.7% 0.5% 0 Sodium dihydrogen phosphate 0 6.2% 10% monohydrate

In one particular embodiment, it was determined that when the amount ofcitric acid is greater than or equal to 1.4, the amount of foam isoptimal when disodium pyrophosphate is present in the compositionaccording to the following equation:[C]=2.4[B]−2.4[A]/0.7when:[C]=weight content of disodium pyrophosphate in the intermediatecomposition A[A]=weight content of citric acid monohydrate in the intermediatecomposition A[B]=weight content of sodium bicarbonate in the intermediate compositionB

The above equation thus makes it possible to calculate the optimumcontents between sodium bicarbonate, citric acid and sodiumpyrophosphate.

Example 5: Comparative Study of Release Profile-Permeation

The aim of this study is to evaluate the penetration and distribution ofvarious formulations according to the invention in human skin.

Study Protocol:

The formulations tested in this study are applied to excised whole humanskin samples mounted on a Franz cell at a rate of 5 mg/cm² at 32° C.

After 16 hours of application, trifarotene is assayed in: the fractionnot absorbed, the stratum corneum, the epidermis, the dermis and thereceiver fluid.

This study makes it possible to study the influence of the formulationon the release of the active principle and its permeation through theskin. The object is to compare the distribution of trifarotene in thevarious skin layers in the case of the application of a well-knownformulation and the application of a composition in chemical foam form.

The formulations tested are:

-   -   Reference in cream form containing 0.01% trifarotene, and    -   A complete chemical foam formulation containing 0.01%        trifarotene, composed of the mixture: A2+B3 (in a 50/50 weight        ratio).

Diffusion Cells:

The diffusion cells used are static diffusion cells, on the basis of theFranz model diffusion cell, with the following characteristics:

-   -   Application area=2 cm²    -   Volume of the receiver fluid compartment=3 ml

The receiver compartment is surrounded by a water jacket heated at 37°C.±1° C. to ensure a temperature of 32° C.±1° C. at the skin surface.The receiver compartment is separated from the donor compartment by theskin membrane, the epidermal face being on the donor side. The receivercompartment containing a magnetic stirring bar was filled with thereceiver fluid so as to prevent any formation of air bubbles. During thediffusion time, the receiver fluid was stirred continuously so as toensure homogenization.

Preparation of the Skin Samples:

Abdominal skin samples derived from cosmetic surgery were used in thisstudy. On arrival of the samples, the hypodermis was separated from theassembly using tweezers, and the remaining material was washed gentlyand stored flat in aluminum foil for storage at −20° C. On the day ofthe experiment, the skin samples were thawed and then cut into pieces tobe compatible with the geometry of the diffusion cell.

The skin samples, derived from donors 42, 44 and 69 years old, weremounted on the diffusion cell with PBS as receiver fluid. The mean skinthickness was 0.89±0.07 mm with a maximum of 1.39 mm and a minimum of0.45 mm. Thicknesses of all the specimens.

After at least 45 minutes at equilibrium with the receiver fluid, theskin integrity was evaluated by measuring the trans-epidermal water loss(TEWL). All the cells whose TEWL measurements were outside theacceptance criteria are carefully cleaned and left at equilibrium for aprolonged period before remeasuring the TEWL. The mean TEWL value was5.51±1.63 g/m²/h.

Study Parameters:

Room temperature: 21.7° C.

Relative humidity 45.6%

Study Results:

In the stratum corneum, there were no significant differences incutaneous penetration between the formulations (foam according to theinvention and cream), as illustrated in FIG. 2.

In the epidermis, the penetration the chemical foam formulations differsvery little from the cream reference (according to example A2+B3 as a50:50 mixture), as illustrated in FIG. 2.

In the dermis, the chemical foam compositions penetrate less than thecream reference (according to example A2+B3 as a 50:50 mixture), asillustrated in FIG. 3.

None of the receiver fluid samples was quantifiable, irrespective of thetest formulation; this suggests low systemic exposure.

The present study confirms the obtaining of a foam which remains on thesurface of the skin, so as to avoid the undesirable effects such asirritation and to obtain a foam which is suitable for the treatment ofacne.

The invention claimed is:
 1. A self-foaming leave-on topical compositioncomprising: (a) at least one intermediate composition B comprising agas-generating agent, wherein the gas-generating agent is selected fromthe group consisting of sodium bicarbonate, potassium bicarbonate,sodium carbonate, and potassium carbonate, and mixtures thereof; (b) atleast one intermediate composition A comprising an agent for activatingthe gas-generating agent, wherein the agent for activating thegas-generating agent is a citric acid/sodium citrate buffer, alone or asa mixture with sodium phosphate and/or disodium pyrophosphate; and (c)0.01% to 0.1% by weight, relative to the weight of the totalcomposition, of trifarotene or a pharmaceutically acceptable saltthereof present in intermediate composition(s) A and/or B; wherein theself-foaming leave-on composition does not comprise any lipophilicemulsifiers.
 2. The composition as claimed in claim 1, wherein thetrifarotene is present in the intermediate composition A.
 3. Thecomposition as claimed in claim 1, wherein the composition does notcomprise any foaming surfactants selected from the group consisting ofanionic surfactants, cationic surfactants, amphoteric surfactants, andnonionic surfactants of the family of alkylpolyglucosides andglucamides.
 4. The composition as claimed in claim 1, wherein the gasgenerated from the gas-generating agent is carbon dioxide.
 5. Thecomposition as claimed in claim 1, wherein the gas-generating agent ispresent in the intermediate composition B in an amount ranging from 1%to 10% by weight, relative to the weight of the intermediate compositionB.
 6. The composition as claimed in claim 1, wherein the intermediatecomposition B has a pH of between 7 and
 12. 7. The composition asclaimed in claim 1, wherein the agent for activating the gas-generatingagent is present in the intermediate composition A in an amount rangingfrom 0.001% to 95% by weight relative to the weight of the intermediatecomposition A.
 8. The composition as claimed in claim 1, wherein theintermediate composition A has an acidic pH.
 9. The composition asclaimed in claim 1, wherein the intermediate composition A is in theform of a solution, a gel, or an emulsion.
 10. The composition asclaimed in claim 1, wherein the intermediate composition B is in theform of a solution, a gel, or an emulsion.
 11. The composition asclaimed in claim 1, wherein the composition is formulated for use in thetreatment of acne.
 12. The composition as claimed in claim 3, whereinthe composition does not comprise any foaming surfactants.
 13. Thecomposition as claimed in claim 1, wherein the gas-generating agent issodium bicarbonate.
 14. The composition as claimed in claim 5, whereinthe gas-generating agent is present in the intermediate composition B inan amount ranging from 2% to 8% by weight.
 15. The composition asclaimed in claim 6, wherein the pH is basic.
 16. The composition asclaimed in claim 8, wherein the acidic pH is from 1.0 to 6.0.
 17. Thecomposition as claimed in claim 9, wherein the intermediate compositionA is in the form of a gel.
 18. The composition as claimed in claim 10,wherein the intermediate composition B is in the form of an emulsion.19. A cosmetic method comprising topically administering an effectiveamount of the self-foaming leave-on topical composition as claimed inclaim 1, to the skin of an individual subject in need thereof.
 20. A kitor single multi-compartment container containing a self-foaming leave-ontopical composition, the composition comprising: (a) at least oneintermediate composition B comprising at least one gas-generating agent,wherein the gas-generating agent is selected from the group consistingof sodium bicarbonate, potassium bicarbonate, sodium carbonate, andpotassium carbonate, and mixtures thereof; (b) at least one intermediatecomposition A comprising at least one agent for activating thegas-generating agent, wherein the agent for activating thegas-generating agent is a citric acid/sodium citrate buffer, alone or asa mixture with sodium phosphate and/or disodium pyrophosphate; and (c)0.01% to 0.1% by weight, relative to the weight of the totalcomposition, of trifarotene or a pharmaceutically acceptable saltthereof present in intermediate composition(s) A and/or B; whereinintermediate compositions A and B are separately contained and generategas upon mixing; and wherein the self-foaming leave-on topicalcomposition does not comprise any lipophilic emulsifiers.
 21. The kit orcontainer as claimed in claim 20, wherein the kit or container isdesigned for mixing the intermediate compositions A and B in an A/Bweight ratio ranging from 0.5 to
 2. 22. The kit or container as claimedin claim 21, wherein the A/B weight ratio ranges from 0.5 to 1.5. 23.The kit or container as claimed in claim 21, wherein the A/B weightratio ranges from 0.9 to 1.1.
 24. The kit or container as claimed inclaim 21, wherein the A/B weight ratio is
 1. 25. A process for preparinga self-foaming leave-on topical composition in foam form, the processcomprising mixing: (a) at least one intermediate composition Bcomprising at least one gas-generating agent, wherein the gas-generatingagent is selected from the group consisting of sodium bicarbonate,potassium bicarbonate, sodium carbonate, and potassium carbonate, andmixtures thereof; and (b) at least one intermediate composition Acomprising at least one agent for activating the gas-generating agent,wherein the agent for activating the gas-generating agent is a citricacid/sodium citrate buffer, alone or as a mixture with sodium phosphateand/or disodium pyrophosphate; wherein trifarotene or a pharmaceuticallyacceptable salt thereof is present in intermediate composition A and/orB at a concentration of 0.01% to 0.1% by weight, relative to the weightof the total composition; and wherein the self-foaming leave-on topicalcomposition does not comprise any lipophilic emulsifiers.
 26. Theprocess as claimed in claim 25, wherein the A/B weight proportion rangesfrom 0.5 to 1.5.
 27. The process as claimed in claim 25, wherein the A/Bweight proportion is
 1. 28. A method for treating acne, comprisingapplying to the skin of a human subject in need thereof a self-foamingcomposition obtained by mixing at least two intermediate compositions,the intermediate compositions comprising: (a) at least one intermediatecomposition B comprising at least one gas-generating agent, wherein thegas-generating agent is selected from the group consisting of sodiumbicarbonate, potassium bicarbonate, sodium carbonate, and potassiumcarbonate, and mixtures thereof; (b) at least one intermediatecomposition A comprising at least one agent for activating thegas-generating agent, wherein the agent for activating thegas-generating agent is a citric acid/sodium citrate buffer, alone or asa mixture with sodium phosphate and/or disodium pyrophosphate; and (c)0.01% to 0.1% by weight, relative to the weight of the totalcomposition, of trifarotene or a pharmaceutically acceptable saltthereof present in intermediate composition(s) A and/or B; wherein theself-foaming composition does not comprise any lipophilic emulsifiers.